Connectomic correlates of response to treatment in first-episode psychosis.

Abstract:Connectomic approaches using diffusion tensor imaging have contributed to our understanding of brain changes in psychosis, and could provide further insights into the neural mechanisms underlying response to antipsychotic treatment. We here studied the brain network organization in patients at their first episode of psychosis, evaluating whether connectome-based descriptions of brain networks predict response to treatment, and whether they change after treatment. Seventy-six patients with a first episode of psychosis and 74 healthy controls were included. Thirty-three patients were classified as responders after 12 weeks of antipsychotic treatment. Baseline brain structural networks were built using whole-brain diffusion tensor imaging tractography, and analysed using graph analysis and network-based statistics to explore baseline characteristics of patients who subsequently responded to treatment. A subgroup of 43 patients was rescanned at the 12-week follow-up, to study connectomic changes over time in relation to treatment response. At baseline, those subjects who subsequently responded to treatment, compared to those that did not, showed higher global efficiency in their structural connectomes, a network configuration that theoretically facilitates the flow of information. We did not find specific connectomic changes related to treatment response after 12 weeks of treatment. Our data suggest that patients who have an efficiently-wired connectome at first onset of psychosis show a better subsequent response to antipsychotics. However, response is not accompanied by specific structural changes over time detectable with this method.

The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment.

Abstract:Bipolar affective disorder is a common neuropsychiatric disorder. Although its neurobiological underpinnings are incompletely understood, the dopamine hypothesis has been a key theory of the pathophysiology of both manic and depressive phases of the illness for over four decades. The increased use of antidopaminergics in the treatment of this disorder and new in vivo neuroimaging and post-mortem studies makes it timely to review this theory. To do this, we conducted a systematic search for post-mortem, pharmacological, functional magnetic resonance and molecular imaging studies of dopamine function in bipolar disorder. Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergia, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania. In bipolar depression imaging studies show increased dopamine transporter levels, but changes in other aspects of dopaminergic function are inconsistent. Puzzlingly, pharmacological evidence shows that both dopamine agonists and antidopaminergics can improve bipolar depressive symptoms and perhaps actions at other receptors may reconcile these findings. Tentatively, this evidence suggests a model where an elevation in striatal D2/3 receptor availability would lead to increased dopaminergic neurotransmission and mania, whilst increased striatal dopamine transporter (DAT) levels would lead to reduced dopaminergic function and depression. Thus, it can be speculated that a failure of dopamine receptor and transporter homoeostasis might underlie the pathophysiology of this disorder. The limitations of this model include its reliance on pharmacological evidence, as these studies could potentially affect other monoamines, and the scarcity of imaging evidence on dopaminergic function. This model, if confirmed, has implications for developing new treatment strategies such as reducing the dopamine synthesis and/or release in mania and DAT blockade in bipolar depression.

Abstract:Background: There is no consensus as to whether magnetic resonance imaging (MRI) should be used as part of the initial clinical evaluation of patients with first-episode psychosis (FEP).
Aims: (a) To assess the logistical feasibility of routine MRI; (b) to define the clinical significance of radiological abnormalities in patients with FEP.
Method: Radiological reports from MRI scans of two FEP samples were reviewed; one comprised 108 patients and 98 healthy controls recruited to a research study and the other comprised 241 patients scanned at initial clinical presentation plus 66 healthy controls.
Results: In the great majority of patients, MRI was logistically feasible. Radiological abnormalities were reported in 6% of the research sample and in 15% of the clinical sample (odds ratio (OR) = 3.1, 95% CI 1.26–7.57, w2(1) = 6.63, P = 0.01). None of the findings necessitated a change in clinical management.
Conclusions: Rates of neuroradiological abnormalities in FEP are likely to be underestimated in research samples that often exclude patients with organic abnormalities. However, the majority of findings do not require intervention.

Kinetic modelling of [11C]PBR28 for 18kDa translocator protein PET data: A validation study of vascular modelling in the brain using XBD173 and tissue analysis.

Abstract:The 18 kDa translocator protein (TSPO) is a marker of microglia activation in the central nervous system and represents the main target of radiotracers for the in vivo quantification of neuroinflammation with positron emission tomography (PET). TSPO PET is methodologically challenging given the heterogeneous distribution of TSPO in blood and brain. Our previous studies with the TSPO tracers [11 C]PBR28 and [11 C]PK11195 demonstrated that a model accounting for TSPO binding to the endothelium improves the quantification of PET data. Here, we performed a validation of the kinetic model with the additional endothelial compartment through a displacement study. Seven subjects with schizophrenia, all highaffinity binders, underwent two [11 C]PBR28 PET scans before and after oral administration of 90 mg of the TSPO ligand XBD173. The addition of the endothelial component provided a signal compartmentalization much more consistent with the underlying biology, as only in this model, the blocking study produced the expected reduction in the tracer concentration of the specific tissue compartment, whereas the non-displaceable compartment remained unchanged. In addition, we also studied TSPO expression in vessels using 3D reconstructions of histological data of frontal lobe and cerebellum, demonstrating that TSPO positive vessels account for 30% of the vascular volume in cortical and white matter.

Abstract:BACKGROUND:
Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection.
METHODS:
We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site.
RESULTS:
Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p<1×10-10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other.
CONCLUSIONS:
The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.

Abstract:There has been much recent debate concerning the relative clinical utility of symptom dimensions versus conventional diagnostic categories in patients with psychosis. We investigated whether symptom dimensions rated at presentation for first-episode psychosis (FEP) better predicted time to first remission than categorical diagnosis over a four-year follow-up. The sample comprised 193 FEP patients aged 18-65years who presented to psychiatric services in South London, UK, between 2006 and 2010. Psychopathology was assessed at baseline with the Positive and Negative Syndrome Scale and five symptom dimensions were derived using Wallwork/Fortgang's model; baseline diagnoses were grouped using DSM-IV codes. Time to start of first remission was ascertained from clinical records. The Bayesian Information Criterion (BIC) was used to find the best fitting accelerated failure time model of dimensions, diagnoses and time to first remission. Sixty percent of patients remitted over the four years following first presentation to psychiatric services, and the average time to start of first remission was 18.3weeks (SD=26.0, median=8). The positive (BIC=166.26), excited (BIC=167.30) and disorganised/concrete (BIC=168.77) symptom dimensions, and a diagnosis of schizophrenia (BIC=166.91) predicted time to first remission. However, a combination of the DSM-IV diagnosis of schizophrenia with all five symptom dimensions led to the best fitting model (BIC=164.35). Combining categorical diagnosis with symptom dimension scores in FEP patients improved the accuracy of predicting time to first remission. Thus our data suggest that the decision to consign symptom dimensions to an annexe in DSM-5 should be reconsidered at the earliest opportunity.

Abstract:Background: Polygenic risk scores (PRSs) have successfully summarized genome-wide effects of genetic variants in schizophrenia with significant predictive power. In a clinical sample of first-episode psychosis (FEP) patients, we estimated the ability of PRSs to discriminate case-control status and to predict the development of schizophrenia as opposed to other psychoses. Method: The sample (445 case and 265 control subjects) was genotyped on the Illumina HumanCore Exome BeadChip with an additional 828 control subjects of African ancestry genotyped on the Illumina Multi-Ethnic Genotyping Array. To calculate PRSs, we used the results from the latest Psychiatric Genomics Consortium schizophrenia meta-analysis. We examined the association of PRSs with case-control status and with schizophrenia versus other psychoses in European and African ancestry FEP patients and in a second sample of 248 case subjects with chronic psychosis. Results: PRS had good discriminative ability of case-control status in FEP European ancestry individuals (9.4% of the variance explained, p < 10-6), but lower in individuals of African ancestry (R2 = 1.1%, p = .004). Furthermore, PRS distinguished European ancestry case subjects who went on to acquire a schizophrenia diagnosis from those who developed other psychotic disorders (R2 = 9.2%, p = .002). Conclusions: PRS was a powerful predictor of case-control status in a European sample of patients with FEP, even though a large proportion did not have an established diagnosis of schizophrenia at the time of assessment. PRS was significantly different between those case subjects who developed schizophrenia from those who did not, although the discriminative accuracy may not yet be sufficient for clinical utility in FEP.

Abstract:Background: Many patients with schizophrenia require high doses of medication for their ongoing psychotic symptoms. Glutamate theories and findings from studies showing efficacy of sarcosine, an endogenous, non-selective glycine-reuptake inhibitor mediated by GlyT1, off er an alternative approach. We undertook the SearchLyte trial programme to examine the efficacy of bitopertin, a selective GlyT1-mediated glycine-reuptake inhibitor, as an adjunctive treatment to ongoing antipsychotic treatment.
Methods: SearchLyte consisted of three phase 3, randomised, double-blind, parallel-group, placebo-controlled, multicentre studies done in outpatient clinics in Asia, Europe, and North and South America (TwiLyte done at 109 sites, NightLyte at 84, and MoonLyte at 87). Participants were male and female outpatients, aged at least 18 years, meeting DSM-IV criteria for schizophrenia with suboptimally controlled positive symptoms despite treatment with antipsychotics. Inclusion criteria included a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and antipsychotic treatment stability for the past 12 weeks before randomisation. Key exclusion criteria included meeting criteria for symptomatic remission or previous treatment with a GlyT1 inhibitor or any other investigational drug. After a screening or 4-week prospective stabilisation period, we randomly assigned participants (1:1:1) to a 12-week, double-blind treatment of either placebo or one of two fixed doses of oral, once-daily bitopertin (10 or 20 mg in TwiLyte and NightLyte; 5 or 10 mg in MoonLyte) added to their current antipsychotic medicine. After completion of 12 weeks’ treatment, the study design allowed for additional double-blind treatment for 40 weeks to assess maintenance of the effect, followed by a randomised 4-week washout period to assess withdrawal effects. Subsequently, all patients were offered the opportunity to receive bitopertin treatment in a 3-year follow-up. The primary efficacy endpoint was the mean change from baseline in the PANSS Positive Symptom Factor Score (PSFS) at week 12, analysed in the modified intention-to-treat population. The trials were registered at ClinicalTrials.gov (numbers NCT01235520 [TwiLyte], NCT01235585 [MoonLyte], and NCT01235559 [NightLyte]).
Findings: Between Nov 19, 2010, and Dec 12, 2014, we randomly assigned 1794 patients to treatment, of whom 1772 were treated and analysed. MoonLyte was discontinued in September, 2014, on the basis of results from futility analyses. Across studies and treatment arms, most patients completed 12 weeks of treatment (505 in TwiLyte, 517 in NightLyte, and 506 in MoonLyte). Only one study, NightLyte, met the primary endpoint where the PANSS PSFS significantly differed from placebo at week 12, and only in the 10-mg arm: mean diff erence in score –1.37, 95% CI –2.27 to –0.47; p=0.0028. Improvements from baseline for the bitopertin 20-mg arm in Nightlyte were not significant compared with placebo: –3.77, 95% CI –4.40 to –3.14; p=0.3142. Results from the other two studies also did not diff er from placebo (TwiLyte 0.58, 95% CI –0.34 to 1.50, p=0.22 for 10 mg and 0.43, –0.49 to 1.36, p=0.36 for 20 mg; MoonLyte 0.06, 95% CI –0.79 to 0.92, p=0.88 for 5 mg and 0.44, –0.41 to 1.28, p=0.31 for 10 mg). Placebo responses varied across studies and might have contributed to the differences in efficacy between studies. Four deaths occurred during the 12-week treatment period, three in NightLyte (upper gastrointestinal haemorrhage, alcohol poisoning and related head injury, and a completed suicide) and one in MoonLyte (myocardial infarction in a patient with pre-existing risk factors). Only the death by suicide was deemed related to the study drug. The incidence of serious adverse events was low across treatment groups in all three studies; psychiatric disorders were the most frequently reported serious adverse events and the most frequent cause of adverse events leading to discontinuation.
Interpretation: Only one of six active treatment arms across the three studies offered an advantage of adjunctive bitopertin over placebo for the treatment of suboptimally controlled symptoms of schizophrenia. The small improvement associated with bitopertin together with the varying placebo response suggests that adjunctive bitopertin treatment might offer only modest benefit to suboptimal responders to antipsychotics, if any.

Effects of antipsychotics on cortisol, interleukin-6 and hippocampal perfusion in healthy volunteers

Abstract:This randomized within-subject, double blind study aimed to compare the effects of a single dose of two different antipsychotics (haloperidol and aripiprazole) on cortisol, interleukin (IL)-6 and hippocampal regional Cerebral Blood Flow (rCBF) in the same 17 healthy male individuals. Subjects received a single dose of haloperidol (3mg), aripiprazole (10mg) and placebo, in a randomized order on three study appointments. We measured salivary cortisol levels at multiple time points, IL-6 levels from plasma samples, and resting cerebral blood flow (rCBF), using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T). We found significantly lower cortisol levels in the haloperidol condition (F(2,32)=5.78, p=0.007), than in either placebo (p=0.013; CI=0.45, 0.406) or aripiprazole (p=0.037; CI=-0.520, -0.014). Interleukin-6 levels were also lower following haloperidol (F(2,22)=4.19, p=0.048) in comparison with placebo (p=0.02; CI=0.14, 1.8), but not with aripiprazole. Finally, we found a greater rCBF in the right (peak voxel: T=6.47, p<0.0001) and left (peak voxel T=5.17, p<0.01) hippocampus following haloperidol compared with placebo, and at trend level also in the left hippocampus following aripiprazole compared with placebo (T=4.07, p=0.057). These differences in hippocampal rCBF after both antipsychotics were no longer evident (haloperidol) or present at trend level (aripiprazole), after controlling for cortisol and IL-6 levels. Our findings suggest that haloperidol can directly regulate the hypothalamic-pituitary-adrenal (HPA) axis and immune system through a pharmacological action via D2 receptor antagonism. Finally, our data suggest that the increased hippocampal rCBF is a manifestation of the reduction in IL-6 and cortisol which follows the administration of haloperidol.

Abstract:Background: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. Method: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. Results: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. Conclusions: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.

Effects of aripiprazole and haloperidol on neural activation during a simple motor task in healthy individuals: A functional MRI study.

Abstract:The dopaminergic system plays a key role in motor function and motor abnormalities have been shown to be a specific feature of psychosis. Due to their dopaminergic action, antipsychotic drugs may be expected to modulate motor function, but the precise effects of these drugs on motor function remain unclear. We carried out a within-subject, double-blind, randomized study of the effects of aripiprazole, haloperidol and placebo on motor function in 20 healthy men. For each condition, motor performance on an auditory-paced task was investigated. We entered maps of neural activation into a random effects general linear regression model to investigate motor function main effects. Whole-brain imaging revealed a significant treatment effect in a distributed network encompassing posterior orbitofrontal/anterior insula cortices, and the inferior temporal and postcentral gyri. Post-hoc comparison of treatments showed neural activation after aripiprazole did not differ significantly from placebo in either voxel-wise or region of interest analyses, with the results above driven primarily by haloperidol. We also observed a simple main effect of haloperidol compared with placebo, with increased task-related recruitment of posterior cingulate and precentral gyri. Furthermore, region of interest analyses revealed greater activation following haloperidol compared with placebo in the precentral and post-central gyri, and the putamen. These diverse modifications in cortical motor activation may relate to the different pharmacological profiles of haloperidol and aripiprazole, although the specific mechanisms underlying these differences remain unclear. Evaluating healthy individuals can allow investigation of the effects of different antipsychotics on cortical activation, independently of either disease-related pathology or previous treatment.

Abstract:Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species.

Effect of high-potency cannabis on corpus callosum microstructure

Abstract:Background: The use of cannabis with higher Δ9-tetrahydrocannabinol content has been associated with greater risk, and earlier onset, of psychosis. However, the effect of cannabis potency on brain morphology has never been explored. Here, we investigated whether cannabis potency and pattern of use are associated with changes in corpus callosum (CC) microstructural organization, in patients with first-episode psychosis (FEP) and individuals without psychosis, cannabis users and non-users. Method: The CC of 56 FEP (37 cannabis users) and 43 individuals without psychosis (22 cannabis users) was virtually dissected and segmented using diffusion tensor imaging tractography. The diffusion index of fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity was calculated for each segment. Results: Across the whole sample, users of high-potency cannabis had higher total CC MD and higher total CC AD than both low-potency users and those who never used (p = 0.005 and p = 0.004, respectively). Daily users also had higher total CC MD and higher total CC AD than both occasional users and those who never used (p = 0.001 and p < 0.001, respectively). However, there was no effect of group (patient/individuals without psychosis) or group x potency interaction for either potency or frequency of use. The within-group analysis showed in fact that the effects of potency and frequency were similar in FEP users and in users without psychosis. Conclusions: Frequent use of high-potency cannabis is associated with disturbed callosal microstructural organization in individuals with and without psychosis. Since high-potency preparations are now replacing traditional herbal drugs in many European countries, raising awareness about the risks of high-potency cannabis is crucial.

Abstract:Background: Many patients with schizophrenia require high doses of medication for their ongoing psychotic symptoms. Glutamate theories and findings from studies showing efficacy of sarcosine, an endogenous, non-selective glycine-reuptake inhibitor mediated by GlyT1, offer an alternative approach. We undertook the SearchLyte trial programme to examine the efficacy of bitopertin, a selective GlyT1-mediated glycine-reuptake inhibitor, as an adjunctive treatment to ongoing antipsychotic treatment. Method: SearchLyte consisted of three phase 3, randomised, double-blind, parallel-group, placebo-controlled, multicentre studies done in outpatient clinics in Asia, Europe, and North and South America (TwiLyte done at 109 sites, NightLyte at 84, and MoonLyte at 87). Participants were male and female outpatients, aged at least 18 years, meeting DSM-IV criteria for schizophrenia with suboptimally controlled positive symptoms despite treatment with antipsychotics. Inclusion criteria included a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and antipsychotic treatment stability for the past 12 weeks before randomisation. Key exclusion criteria included meeting criteria for symptomatic remission or previous treatment with a GlyT1 inhibitor or any other investigational drug. After a screening or 4-week prospective stabilisation period, we randomly assigned participants (1:1:1) to a 12-week, double-blind treatment of either placebo or one of two fixed doses of oral, once-daily bitopertin (10 or 20 mg in TwiLyte and NightLyte; 5 or 10 mg in MoonLyte) added to their current antipsychotic medicine. After completion of 12 weeks' treatment, the study design allowed for additional double-blind treatment for 40 weeks to assess maintenance of the effect, followed by a randomised 4-week washout period to assess withdrawal effects. Subsequently, all patients were offered the opportunity to receive bitopertin treatment in a 3-year follow-up. The primary efficacy endpoint was the mean change from baseline in the PANSS Positive Symptom Factor Score (PSFS) at week 12, analysed in the modified intention-to-treat population. The trials were registered at ClinicalTrials.gov (numbers NCT01235520 [TwiLyte], NCT01235585 [MoonLyte], and NCT01235559 [NightLyte]). Results: Between Nov 19, 2010, and Dec 12, 2014, we randomly assigned 1794 patients to treatment, of whom 1772 were treated and analysed. MoonLyte was discontinued in September, 2014, on the basis of results from futility analyses. Across studies and treatment arms, most patients completed 12 weeks of treatment (505 in TwiLyte, 517 in NightLyte, and 506 in MoonLyte). Only one study, NightLyte, met the primary endpoint where the PANSS PSFS significantly differed from placebo at week 12, and only in the 10-mg arm: mean difference in score -1•37, 95% CI -2•27 to -0•47; p=0•0028. Improvements from baseline for the bitopertin 20-mg arm in Nightlyte were not significant compared with placebo: -3•77, 95% CI -4•40 to -3•14; p=0•3142. Results from the other two studies also did not differ from placebo (TwiLyte 0•58, 95% CI -0•34 to 1•50, p=0•22 for 10 mg and 0•43, -0•49 to 1•36, p=0•36 for 20 mg; MoonLyte 0•06, 95% CI -0•79 to 0•92, p=0•88 for 5 mg and 0•44, -0•41 to 1•28, p=0•31 for 10 mg). Placebo responses varied across studies and might have contributed to the differences in efficacy between studies. Four deaths occurred during the 12-week treatment period, three in NightLyte (upper gastrointestinal haemorrhage, alcohol poisoning and related head injury, and a completed suicide) and one in MoonLyte (myocardial infarction in a patient with pre-existing risk factors). Only the death by suicide was deemed related to the study drug. The incidence of serious adverse events was low across treatment groups in all three studies; psychiatric disorders were the most frequently reported serious adverse events and the most frequent cause of adverse events leading to discontinuation. Conclusions: Only one of six active treatment arms across the three studies offered an advantage of adjunctive bitopertin over placebo for the treatment of suboptimally controlled symptoms of schizophrenia. The small improvement associated with bitopertin together with the varying placebo response suggests that adjunctive bitopertin treatment might offer only modest benefit to suboptimal responders to antipsychotics, if any.

Abstract:Background: Converging evidence suggests that patients with first-episode psychosis who show a poor treatment response may have a higher degree of neurodevelopmental abnormalities than good Responders. Characterizing the disturbances in the relationship among brain regions (covariance) can provide more information on neurodevelopmental integrity than searching for localized changes in the brain. Graph-based connectomic approach can measure structural covariance thus providing information on the maturational processes. We quantified the structural covariance of cortical folding using graph theory in first-episode psychosis, to investigate if this systems-level approach would improve our understanding of the biological determinants of outcome in psychosis. Method: Magnetic Resonance Imaging data were acquired in 80 first-episode psychosis patients and 46 healthy controls. Response to treatment was assessed after 12 weeks of naturalistic follow-up. Gyrification-based connectomes were constructed to study the maturational organization of cortical folding. Results: Nonresponders showed a reduction in the distributed relationship among brain regions (high segregation, poor integration) when compared to Responders and controls, indicating a higher burden of aberrant neurodevelopment. They also showed reduced centrality of key regions (left insula and anterior cingulate cortex) indicating a marked reconfiguration of gyrification. Nonresponders showed a vulnerable pattern of covariance that disintegrated when simulated lesions removed high-degree hubs, indicating an abnormal dependence on highly central hub regions in Nonresponders. Conclusions: These findings suggest that a perturbed maturational relationship among brain regions underlies poor treatment response in first-episode psychosis. The information obtained from gyrification-based connectomes can be harnessed for prospectively predicting treatment response and prognosis in psychosis.

Phosphodiesterase 10A in Schizophrenia: A PET Study Using [(11)C]IMA107

Abstract:Background: Phosphodiesterase 10A (PDE10A) is an enzyme present in striatal medium spiny neurons that degrades the intracellular second messengers triggered by dopamine signaling. The pharmaceutical industry has considerable interest in PDE10A inhibitors because they have been shown to have an antipsychotic-like effect in animal models. However, the status of PDE10A in schizophrenia is unknown. Using a newly developed and validated radioligand, [(11)C]IMA107, the authors report the first in vivo assessment of PDE10A brain expression in patients with schizophrenia. Method: The authors compared PDE10A availability in the brains of 12 patients with chronic schizophrenia and 12 matched healthy comparison subjects using [(11)C]IMA107 positron emission tomography (PET). Regional estimates of the binding potential (BPND) of [(11)C]IMA107 were generated from dynamic PET scans using the simplified reference tissue model with the cerebellum as the reference tissue for nonspecific binding. Results: There was no significant difference in [(11)C]IMA107 BPND between schizophrenia patients and comparison subjects in any of the brain regions studied (thalamus, caudate, putamen, nucleus accumbens, globus pallidus, and substantia nigra). There was also no significant correlation between [(11)C]IMA107 BPND and the severity of psychotic symptoms or antipsychotic dosage. Conclusions: Patients with schizophrenia have normal availability of PDE10A in brain regions thought to be involved in the pathophysiology of this disorder. The findings do not support the proposal of an altered PDE10A availability in schizophrenia. The implication of this finding for future drug development is discussed.

Abstract:Huntington's disease (HD) is a monogenic neurodegenerative disorder with an underlying pathology involving the toxic effect of mutant huntingtin protein primarily in striatal and cortical neurons. Phosphodiesterase 10A (PDE10A) regulates intracellular signalling cascades, thus having a key role in promoting neuronal survival. Using positron emission tomography (PET) with [11C]IMA107, we investigated the in vivo extra-striatal expression of PDE10A in 12 early premanifest HD gene carriers. Image processing and kinetic modellingwas performed using MIAKAT™. Parametric images of [11C]IMA107 non-displaceable binding potential (BPND) were generated fromthe dynamic [11C]IMA107 scans using the simplified reference tissue model with the cerebellumas the reference tissue for nonspecific binding.We set a threshold criterion for meaningful quantification of [11C]IMA107 BPND at 0.30 in healthy control data; regions meeting this criterion were designated as regions of interest (ROIs). MRI-based volumetric analysis showed no atrophy in ROIs. We found significant differences in mean ROIs [11C]IMA107 BPND between HD gene carriers and healthy controls. HD gene carriers had significant loss of PDE10A within the insular cortex and occipital fusiform gyrus compared to healthy controls. Insula and occipital fusiformgyrus are important brain areas for the regulation of cognitive and limbic function that is impaired inHD. Our findings suggest that dysregulation of PDE10A-mediated intracellular signalling could be an early phenomenon in the course of HD with relevance also for extra-striatal brain areas.

Abstract:Background: Polygenic risk scores (PRSs) have successfully summarized genome-wide effects of genetic variants in schizophrenia with significant predictive power. In a clinical sample of first-episode psychosis (FEP) patients, we estimated the ability of PRSs to discriminate case-control status and to predict the development of schizophrenia as opposed to other psychoses.
Methods: The sample (445 case and 265 control subjects) was genotyped on the Illumina HumanCore Exome BeadChip with an additional 828 control subjects of African ancestry genotyped on the Illumina Multi-Ethnic Genotyping Array. To calculate PRSs, we used the results from the latest Psychiatric Genomics Consortium schizophrenia meta-analysis. We examined the association of PRSs with case-control status and with schizophrenia versus other psychoses in European and African ancestry FEP patients and in a second sample of 248 case subjects with chronic psychosis.
Results: PRS had good discriminative ability of case-control status in FEP European ancestry individuals (9.4% of the variance explained, p , 1026), but lower in individuals of African ancestry (R2 5 1.1%, p 5 .004). Furthermore, PRS distinguished European ancestry case subjects who went on to acquire a schizophrenia diagnosis from those who developed other psychotic disorders (R2 5 9.2%, p 5 .002).
Conclusions: PRS was a powerful predictor of case-control status in a European sample of patients with FEP, even though a large proportion did not have an established diagnosis of schizophrenia at the time of assessment. PRS was significantly different between those case subjects who developed schizophrenia from those who did not, although the discriminative accuracy may not yet be sufficient for clinical utility in FEP.

Abstract:Background: Clozapine remains the only evidence-based antipsychotic for treatment-resistant schizophrenia (TRS). The ability to predict which patients with their first onset of schizophrenia would subsequently meet criteria for treatment resistance (TR) could help to diminish the severe functional disability which may ensue if TR is not recognized and correctly treated.
Method: This is a 5-year longitudinal assessment of clinical outcomes in a cohort of 246 first-episode schizophrenia spectrum patients recruited as part of the NIHR Genetics and Psychosis (GAP) study conducted in South London from 2005 to 2010.We examined the relationship between baseline demographic and clinical measures and the emergence of TR. TR status was determined from a review of electronic case records. We assessed for associations with early-, and late-onset TR, and non-TR, and differences between those TR patients treated with clozapine and those who were not.
Results: Seventy per cent (n = 56) of TR patients, and 23% of the total study population (n = 246) were treatment resistant from illness onset. Those who met criteria for TR during the first 5 years of illness were more likely to have an early age of first contact for psychosis (<20 years) [odds ratio (OR) 2.49, 95% confidence interval (CI) 1.25–4.94] compared to those with non-TR. The relationship between an early age of first contact (<20 years) and TR was significant in patients of Black ethnicity (OR 3.71, 95% CI 1.44–9.56); and patients of male gender (OR 3.13 95% CI 1.35–7.23).
Conclusions: For the majority of the TR group, antipsychotic TR is present from illness onset, necessitating increased consideration for the earlier use of clozapine.

Abstract:Background: Converging evidence suggests that patients with first-episode psychosis who show a poor treatment response may have a higher degree of neurodevelopmental abnormalities than good Responders. Characterizing the disturbances in the relationship among brain regions (covariance) can provide more information on neurodevelopmental integrity than searching for localized changes in the brain. Graph-based connectomic approach can measure structural covariance thus providing information on the maturational processes. We quantified the structural covariance of cortical folding using graph theory in first-episode psychosis, to investigate if this systems-level approach would improve our understanding of the biological determinants of outcome in psychosis.
Methods: Magnetic Resonance Imaging data were acquired in 80 first-episode psychosis patients and 46 healthy controls. Response to treatment was assessed after 12 weeks of naturalistic follow-up. Gyrification-based connectomes were constructed to study the maturational organization of cortical folding.
Results: Nonresponders showed a reduction in the distributed relationship among brain regions (high segregation, poor integration) when compared to Responders and controls, indicating a higher burden of aberrant neurodevelopment. They also showed reduced centrality of key regions (left insula and anterior cingulate cortex) indicating a marked reconfiguration of gyrification. Nonresponders showed a vulnerable pattern of covariance that disintegrated when simulated lesions removed high-degree hubs, indicating an abnormal dependence on highly central hub regions in Nonresponders.
Conclusions: These findings suggest that a perturbed maturational relationship among brain regions underlies poor treatment response in firstepisode psychosis. The information obtained from gyrification- based connectomes can be harnessed for prospectively predicting treatment response and prognosis in psychosis.

Abstract:Objective: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines.
Method: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus.
Results: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients.
Conclusions: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.

Abstract:Background: Clozapine remains the only evidence-based antipsychotic for treatment-resistant schizophrenia (TRS). The ability to predict which patients with their first onset of schizophrenia would subsequently meet criteria for treatment resistance (TR) could help to diminish the severe functional disability which may ensue if TR is not recognized and correctly treated. Method: This is a 5-year longitudinal assessment of clinical outcomes in a cohort of 246 first-episode schizophrenia spectrum patients recruited as part of the NIHR Genetics and Psychosis (GAP) study conducted in South London from 2005 to 2010. We examined the relationship between baseline demographic and clinical measures and the emergence of TR. TR status was determined from a review of electronic case records. We assessed for associations with early-, and late-onset TR, and non-TR, and differences between those TR patients treated with clozapine and those who were not. Results: Seventy per cent (n = 56) of TR patients, and 23% of the total study population (n = 246) were treatment resistant from illness onset. Those who met criteria for TR during the first 5 years of illness were more likely to have an early age of first contact for psychosis (<20 years) [odds ratio (OR) 2.49, 95% confidence interval (CI) 1.25-4.94] compared to those with non-TR. The relationship between an early age of first contact (<20 years) and TR was significant in patients of Black ethnicity (OR 3.71, 95% CI 1.44-9.56); and patients of male gender (OR 3.13 95% CI 1.35-7.23). Conclusions: For the majority of the TR group, antipsychotic TR is present from illness onset, necessitating increased consideration for the earlier use of clozapine.

Abstract:Huntington's disease (HD) is a monogenic neurodegenerative disorder with an underlying pathology involving the toxic effect of mutant huntingtin protein primarily in striatal and cortical neurons. Phosphodiesterase 10A (PDE10A) regulates intracellular signalling cascades, thus having a key role in promoting neuronal survival. Using positron emission tomography (PET) with [(11)C]IMA107, we investigated the in vivo extra-striatal expression of PDE10A in 12 early premanifest HD gene carriers. Image processing and kinetic modelling was performed using MIAKAT™. Parametric images of [(11)C]IMA107 non-displaceable binding potential (BPND) were generated from the dynamic [(11)C]IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue for nonspecific binding. We set a threshold criterion for meaningful quantification of [(11)C]IMA107 BPND at 0.30 in healthy control data; regions meeting this criterion were designated as regions of interest (ROIs). MRI-based volumetric analysis showed no atrophy in ROIs. We found significant differences in mean ROIs [(11)C]IMA107 BPND between HD gene carriers and healthy controls. HD gene carriers had significant loss of PDE10A within the insular cortex and occipital fusiform gyrus compared to healthy controls. Insula and occipital fusiform gyrus are important brain areas for the regulation of cognitive and limbic function that is impaired in HD. Our findings suggest that dysregulation of PDE10A-mediated intracellular signalling could be an early phenomenon in the course of HD with relevance also for extra-striatal brain areas.

A Neuroanatomical Signature for Schizophrenia Across Different Ethnic Groups

Abstract:Schizophrenia is a disabling clinical syndrome found across the world. While the incidence and clinical expression of this illness are strongly influenced by ethnic factors, it is unclear whether patients from different ethnicities show distinct brain deficits. In this multicentre study, we used structural Magnetic Resonance Imaging to investigate neuroanatomy in 126 patients with first episode schizophrenia who came from 4 ethnically distinct cohorts (White Caucasians, African-Caribbeans, Japanese, and Chinese). Each patient was individually matched with a healthy control of the same ethnicity, gender, and age (±1 year). We report a reduction in the gray matter volume of the right anterior insula in patients relative to controls (P < .05 corrected); this reduction was detected in all 4 ethnic groups despite differences in psychopathology, exposure to antipsychotic medication and image acquisition sequence. This finding provides evidence for a neuroanatomical signature of schizophrenia expressed above and beyond ethnic variations in incidence and clinical expression. In light of the existing literature, implicating the right anterior insula in bipolar disorder, depression, addiction, obsessive-compulsive disorder, and anxiety, we speculate that the neuroanatomical deficit reported here may represent a transdiagnostic feature of Axis I disorders.

Abstract:Background: The satisfaction with the medical profession has been identified as an essential factor for the quality of care, the wellbeing of patients and the healthcare systems' stability. Recent studies have emphasized a growing discontent of physicians, mainly as a result of changes in labor relations. Objectives: To assess the perception of Portuguese medical residents about: correspondence of residency with previous expectations; degree of satisfaction with the specialty, profession and place of training; reasons for dissatisfaction; opinion regarding clinical practice in Portugal and emigration intents. Method: Cross-sectional study. Data collection was conducted through the "Satisfaction with Specialization Survey", created in an online platform, designed for this purpose, between May and August 2014. Results: From a total population of 5788 medical residents, 804 (12.25 %) responses were obtained. From this sample, 77% of the responses were from residents in the first three years. Results showed that 90% of the residents are satisfied with their specialty, 85% with the medical profession and 86% with their place of training. Nevertheless, results showed a decrease in satisfaction over the final years of residency. The overall assessment of the clinical practice scenario in Portugal was negative and 65% of residents have plans to emigrate after completing their residency. Conclusions: Portuguese residents revealed high satisfaction levels regarding their profession. However, their views on Portuguese clinical practice and the results concerning the intent to emigrate highlight the need to take steps to reverse this scenario.

Abstract:There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers.

Abstract:Background: The risk of individuals having adverse effects from drug use (eg, alcohol) generally depends on the frequency of use and potency of the drug used. We aimed to investigate how frequent use of skunk-like (high-potency) cannabis in south London affected the association between cannabis and psychotic disorders. Methods: We applied adjusted logistic regression models to data from patients aged 18–65 years presenting to South London and Maudsley NHS Foundation Trust with first-episode psychosis and population controls recruited from the same area of south London (UK) to estimate the effect of the frequency of use, and type of cannabis used on the risk of psychotic disorders. We then calculated the proportion of new cases of psychosis attributable to different types of cannabis use in south London. Findings: Between May 1, 2005, and May 31, 2011, we obtained data from 410 patients with first-episode psychosis and 370 population controls. The risk of individuals having a psychotic disorder showed a roughly three-times increase in users of skunk-like cannabis compared with those who never used cannabis (adjusted odds ratio [OR] 2•92, 95% CI 1•52–3•45, p=0•001). Use of skunk-like cannabis every day conferred the highest risk of psychotic disorders compared with no use of cannabis (adjusted OR 5•4, 95% CI 2•81–11•31, p=0•002). The population attributable fraction of first-episode psychosis for skunk use for our geographical area was 24% (95% CI 17–31), possibly because of the high prevalence of use of high-potency cannabis (218 [53%] of 410 patients) in our study. Interpretation: The ready availability of high potency cannabis in south London might have resulted in a greater proportion of first onset psychosis cases being attributed to cannabis use than in previous studies.

Abstract:Abstract
OBJECTIVE:
Antipsychotic drugs target neurotransmitter systems that play key roles in working memory. Therefore, they may be expected to modulate this cognitive function via their actions at receptors for these neurotransmitters. However, the precise effects of antipsychotic drugs on working memory function remain unclear. Most studies have been carried out in clinical populations, making it difficult to disentangle pharmacologicaleffects from pathology-related brain activation. In this study, we aim to investigate the effects of two antipsychotic compounds on brain activationduring working memory in healthy individuals. This would allow elucidation of the effects of current antipsychotic treatments on brain function, independently of either previous antipsychotic use or disease-related pathology.
METHODS:
We carried out a fully counterbalanced, randomised within-subject, double-blinded and placebo-controlled, cross-over study of the effectsof two antipsychotic drugs on working memory function in 17 healthy individuals, using the n-back task. Participants completed the functional MRItask on three separate occasions (in randomised order): following placebo, haloperidol, and aripiprazole. For each condition, working memory ability was investigated, and maps of neural activation were entered into a random effects general linear regression model to investigate main working memory function and linear load. Voxel-wise and region of interest analyses were conducted to attain regions of altered brain activation for each intervention.
RESULTS:
Aripiprazole did not lead to any changes in neural activation compared with placebo. However, reaction time to a correct response was significantly increased following aripiprazole compared to both placebo (p=0.046) and haloperidol (p=0.02). In contrast, compared to placebo,haloperidol dampened activation in parietal (BA 7/40; left: FWE-corr. p=0.005; FWE-corr. right: p=0.007) and frontal (including prefrontal; BA 9/44/46; left: FWE-corr. p=0.009; right: FWE-corr. p=0.014) cortices and the left putamen (FWE-corr. p=0.004). Compared with aripiprazole, haloperidoldampened activation in parietal cortex (BA7/40; left: FWE-corr. p=0.034; right: FWE-corr. p=0.045) and the left putamen (FWE-corr.p=0.015).Haloperidol had no effect on working memory performance compared with placebo.
CONCLUSION:
Cognitive functions are known to be impaired in schizophrenia and as such are an important target of treatments. Elucidating the mechanisms by which antipsychotic medications alter brain activation underlying cognition is essential to advance pharmacological treatment of this disorder. Studies in healthy individuals can help elucidate some of these mechanisms, whilst limiting the confounding effect of the underlying disease-related pathology. Our study provides evidence for immediate and differential effects of single-dose haloperidol and aripiprazole on brain activationduring working memory in healthy individuals. We propose that these differences likely reflect their different receptor affinity profiles, although the precise mechanisms underlying these differences remain unclear.

Abstract:Abstract
A large proportion of individuals with schizophrenia show an inadequate response to treatment with antipsychotics. It can be unclear whether this
is secondary to subtherapeutic antipsychotic plasma levels or to medication ineffectiveness. The purpose of the present study was to determine the
extent of subtherapeutic antipsychotic plasma levels in a group of patients clinically identified as treatment-resistant. In addition we investigated the
frequency of antipsychotic plasma level monitoring in standard clinical practice. Antipsychotic plasma levels were measured in 36 patients identified
as having treatment-resistant schizophrenia by their treating clinicians. Sixteen (44%) patients showed either undetectable (19%) or subtherapeutic
levels (25%), and 20 (56%) patients had levels in the therapeutic range. Subtherapeutic plasma levels were significantly associated with black
ethnicity, shorter duration of current treatment and antipsychotics other than olanzapine and amisulpride. Antipsychotic plasma levels had been
measured in only one patient in the year prior to our study. We found over one-third of patients identified as treatment-resistant have subtherapeutic
antipsychotic levels. This indicates that they may be under-treated rather than treatment-resistant, and thus should receive different management.
Currently the measurement of antipsychotic levels may be under-utilised.

Abstract:Background: Cortisol and inflammatory markers have been increasingly reported as abnormal at psychosis onset. The main aim of our study was to investigate the ability of these biomarkers to predict treatment response at 12 weeks follow-up in first episode psychosis. Methods: In a longitudinal study, we collected saliva and blood samples in 68 first episode psychosis patients (and 57 controls) at baseline and assessed response to clinician-led antipsychotic treatment after 12 weeks. Moreover, we repeated biological measurements in 39 patients at the same time we assessed the response. Saliva samples were collected at multiple time points during the day to measure diurnal cortisol levels and cortisol awakening response (CAR); interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-α, and interferon-γ (IFN-γ) levels were analyzed from serum samples. Patients were divided into Non-Responders (n = 38) and Responders (n = 30) according to the Remission symptom criteria of the Schizophrenia Working Group Consensus. Results: At first onset, Non- Responders had markedly lower CAR (d = 0.6, P = .03) and higher IL-6 and IFN-γ levels (respectively, d = 1.0, P = .003 and d = 0.9, P = .02) when compared with Responders. After 12 weeks, Non-Responders show persistent lower CAR (P = .01), and higher IL-6 (P = .04) and IFN-γ (P= .05) when compared with Responders. Comparison with controls show that these abnormalities are present in both patients groups, but are more evident in Non-Responders. Conclusions: Cortisol and inflammatory biomarkers at the onset of psychosis should be considered as possible predictors of treatment response, as well as potential targets for the development of novel therapeutic agents.

White matter integrity as a predictor of response to treatment in first episode psychosis.

Abstract:The integrity of brain white matter connections is central to a patient's ability to respond to pharmacological interventions. This study tested this hypothesis using a specific measure of white matter integrity, and examining its relationship to treatment response using a prospective design in patients within their first episode of psychosis. Diffusion tensor imaging data were acquired in 63 patients with first episode psychosis and 52 healthy control subjects (baseline). Response was assessed after 12 weeks and patients were classified as responders or non-responders according to treatment outcome. At this second time-point, they also underwent a second diffusion tensor imaging scan. Tract-based spatial statistics were used to assess fractional anisotropy as a marker of white matter integrity. At baseline, non-responders showed lower fractional anisotropy than both responders and healthy control subjects (P < 0.05; family-wise error-corrected), mainly in the uncinate, cingulum and corpus callosum, whereas responders were indistinguishable from healthy control subjects. After 12 weeks, there was an increase in fractional anisotropy in both responders and non-responders, positively correlated with antipsychotic exposure. This represents one of the largest, controlled investigations of white matter integrity and response to antipsychotic treatment early in psychosis. These data, together with earlier findings on cortical grey matter, suggest that grey and white matter integrity at the start of treatment is an important moderator of response to antipsychotics. These findings can inform patient stratification to anticipate care needs, and raise the possibility that antipsychotics may restore white matter integrity as part of the therapeutic response.

Abstract:OBJECTIVES:Cannabis use is associated with an earlier age of onset of psychosis (AOP). However, the reasons for this remain debated.METHODS:We applied a Cox proportional hazards model to 410 first-episode psychosis patients to investigate the association between gender, patterns of cannabis use, and AOP.RESULTS:Patients with a history of cannabis use presented with their first episode of psychosis at a younger age (mean years = 28.2, SD = 8.0; median years = 27.1) than those who never used cannabis (mean years = 31.4, SD = 9.9; median years = 30.0; hazard ratio [HR] = 1.42; 95% CI: 1.16-1.74; P < .001). This association remained significant after controlling for gender (HR = 1.39; 95% CI: 1.11-1.68; P < .001). Those who had started cannabis at age 15 or younger had an earlier onset of psychosis (mean years = 27.0, SD = 6.2; median years = 26.9) than those who had started after 15 years (mean years = 29.1, SD = 8.5; median years = 27.8; HR = 1.40; 95% CI: 1.06-1.84; P = .050). Importantly, subjects who had been using high-potency cannabis (skunk-type) every day had the earliest onset (mean years = 25.2, SD = 6.3; median years = 24.6) compared to never users among all the groups tested (HR = 1.99; 95% CI: 1.50- 2.65; P < .0001); these daily users of high-potency cannabis had an onset an average of 6 years earlier than that of non-cannabis users.CONCLUSIONS:Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users.

Abstract:BACKGROUND:Four novel phosphodiesterase 10A (PDE10A) PET tracers have been synthesized, characterized in preclinical studies, and compared with the previously reported (11)C-MP-10.METHODS::On the basis of in vitro data, IMA102, IMA104, IMA107, and IMA106 were identified as potential PDE10A radioligand candidates and labeled with either (11)C via N-methylation or with (18)F through an SN2 reaction, in the case of IMA102. These candidates were compared with (11)C-MP-10 in pilot in vivo studies in the pig brain. On the basis of these data, (11)C-IMA106 and (11)C-IMA107 were taken into further evaluation and comparison with (11)C-MP-10 in the primate brain. Finally, the most promising radioligand candidate was progressed into human evaluation.RESULTS::All 5 tracers were produced with good radiochemical yield and specific activity. All candidates readily entered the brain and demonstrated a heterogeneous distribution consistent with the known expression of PDE10A. Baseline PET studies in the pig and baboon showed that (11)C-IMA107 and (11)C-MP-10 displayed the most favorable tissue kinetics and imaging properties. The administration of selective PDE10A inhibitors reduced the binding of (11)C-IMA107 and (11)C-MP-10 in the PDE10A-rich brain regions, in a dose-dependent manner. In the nonhuman primate brain, the tissue kinetics of (11)C-IMA107 and (11)C-MP-10 were well described by a 2-tissue-compartment model, allowing robust estimates of the regional total volume of distribution. Blockade with unlabeled MP-10 confirmed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential as the outcome measure of specific binding.CONCLUSION::(11)C-IMA107 was identified as the ligand with the highest binding potential while still possessing reversible kinetics. The first human administration of (11)C-IMA107 has demonstrated the expected regional distribution and suitably fast kinetics, indicating that (11)C-IMA107 will be a useful tool for the investigation of PDE10A status in the living human brain.

How antipsychotics impact the different dimensions of Schizophrenia: a test of competing hypotheses.

Abstract:The clinical expression of schizophrenia is generally reported to be expressed by three to five different factors (i.e. positive, negative, disorganization, excitability, anxiety-depression symptoms). It is often claimed that antipsychotic medications are particularly helpful for positive symptoms, but not for the others, suggesting a differential efficacy for different aspects of the disorder. We formally tested this claim. Using Structural Equation Modeling in two large [1884 patients] clinical trials in schizophrenia, we compared the model of a common general effect of antipsychotics to models whereby the antipsychotics have multiple and differential effects on the different factors of the illness. We validated the generalizability of the model in further trials involving antipsychotics in chronic [1460 patients] and first-episode patients [1053 patients]. Across different populations, different trials and different antipsychotics - the best-fitting model suggests that symptom response in schizophrenia is underpinned by a single general effect with secondary and minor lower-order effects on specific symptom domains. This single-factor model explained nearly 80% of the variance, was superior to the assumption of unique efficacy for specific domains; and replicated across antipsychotics and illness stages. Despite theoretical and pharmacological claims the differential efficacy of antipsychotics on the various dimensions of schizophrenia is not supported in the prevailing data. The implication of this finding for the measurement of treatment response and our understanding of the neurobiology of antipsychotic action, for clinical practice and for future drug development are discussed.

Abstract:BACKGROUND:
Failure to account for the etiological diversity that typically occurs in psychiatric cohorts may increase the potential for confounding as a proportion of genetic variance will be specific to exposures that have varying distributions in cases. This study investigated whether minimizing the potential for such confounding strengthened the evidence for a genetic candidate currently unsupported at the genome-wide level.METHODS:
Two hundred and ninety-one first-episode psychosis cases from South London, UK and 218 unaffected controls were evaluated for a functional polymorphism at the rs1360780 locus in FKBP5. The relationship between FKBP5 and psychosis was modeled using logistic regression. Cannabis use (Cannabis Experiences Questionnaire) and parental separation (Childhood Experience of Care and Abuse Questionnaire) were included as confounders in the analysis.RESULTS:
Association at rs1360780 was not detected until the effects of the two environmental factors had been adjusted for in the model (OR = 2.81, 95% CI 1.23-6.43, p = 0.02). A statistical interaction between rs1360780 and parental separation was confirmed by stratified tests (OR = 2.8, p = 0.02 vs. OR = 0.89, p = 0.80). The genetic main effect was directionally consistent with findings in other (stress-related) clinical phenotypes. Moreover, the variation in effect magnitude was explained by the level of power associated with different cannabis constructs used in the model (r = 0.95).CONCLUSION:
Our results suggest that the extent to which genetic variants in FKBP5 can influence susceptibility to psychosis may depend on other etiological factors. This finding requires further validation in large independent cohorts. Potentially this work could have translational implications; the ability to discriminate between genetic etiologies based on a case-by-case understanding of previous environmental exposures would confer an important clinical advantage that would benefit the delivery of personalizable treatment strategies.

The practical management of refractory schizophrenia - the Maudsley Treatment REview and Assessment Team service approach.

Abstract:OBJECTIVE:
To describe a practical approach to the community management of treatment-resistant schizophrenia (TRS).METHOD:
A descriptive review of an approach to the assessment and management of patients with TRS, including the community titration of clozapine treatment, and a report of the management recommendations for the first one hundred patients assessed by the Treatment REview and Assessment Team (TREAT).RESULTS:
The standardized model for the community assessment, management and titration of clozapine is described. To date, 137 patients have been referred to this service and 100 patients (72%) attended for assessment. Of these, 33 have been initiated on clozapine while fifteen have had clozapine recommended but have not wished to undertake clozapine treatment. Other management options recommended have included augmentation strategies and long-acting injectable antipsychotics.CONCLUSION:
The service had increased the number of patients receiving community assessment and initiation of clozapine by five-fold relative to the rate prior to the establishment of the service. The large number of referrals and high attendance rate indicates that there is clinical demand for the model. Systematic evaluation is required to determine the clinical and cost-effectiveness of this model and its potential application to other clinical settings.

The longitudinal interplay between negative and positive symptom trajectories in patients under antipsychotic treatment: a post hoc analysis of data from a randomized, 1-year pragmatic trial.

Abstract:BACKGROUND:Schizophrenia is a highly heterogeneous disorder with positive and negative symptoms being characteristic manifestations of the disease. While these two symptom domains are usually construed as distinct and orthogonal, little is known about the longitudinal pattern of negative symptoms and their linkage with the positive symptoms. This study assessed the temporal interplay between these two symptom domains and evaluated whether the improvements in these symptoms were inversely correlated or independent with each other.METHODS:This post hoc analysis used data from a multicenter, randomized, open-label, 1-year pragmatic trial of patients with schizophrenia spectrum disorder who were treated with first- and second-generation antipsychotics in the usual clinical settings. Data from all treatment groups were pooled resulting in 399 patients with complete data on both the negative and positive subscale scores from the Positive and Negative Syndrome Scale (PANSS). Individual-based growth mixture modeling combined with interplay matrix was used to identify the latent trajectory patterns in terms of both the negative and positive symptoms. Pearson correlation coefficients were calculated to examine the relationship between the changes of these two symptom domains within each combined trajectory pattern.RESULTS:We identified four distinct negative symptom trajectories and three positive symptom trajectories. The trajectory matrix formed 11 combined trajectory patterns, which evidenced that negative and positive symptom trajectories moved generally in parallel. Correlation coefficients for changes in negative and positive symptom subscale scores were positive and statistically significant (P CONCLUSIONS:This study of symptom trajectories over 1 year shows that changes in negative and positive symptoms were neither inversely nor independently related with each other. The positive association between these two symptom domains supports the notion that different symptom domains in schizophrenia may depend on each other through a unified upstream pathological disease process.

Abstract:IMPORTANCE:At present, no reliable predictors exist to distinguish future responders from nonresponders to treatment during the first episode of psychosis. Among potential neuroimaging predictors of treatment response, gyrification represents an important marker of the integrity of normal cortical development that may characterize, already at illness onset, a subgroup of patients with particularly poor outcome.OBJECTIVE:To determine whether patients with first-episode psychosis who do not respond to 12 weeks of antipsychotic treatment already have significant gyrification defects at illness onset.DESIGN:Case-control study with 12 weeks' longitudinal follow-up to determine treatment response.SETTING:Secondary psychiatric services in an inner-city area (South London, England).PARTICIPANTS:A total of 126 subjects, including 80 patients presenting with first-episode psychosis and 46 healthy controls. Patients were scanned at the outset and received various antipsychotic medications in a naturalistic clinical setting. They were followed up for 12 weeks and classified as responders or nonresponders if they reached criteria for symptom remission, evaluated with the Psychiatric and Personal History Schedule.OBSERVATION:Patients were exposed to naturalistic antipsychotic treatment for 12 weeks following a magnetic resonance imaging scan.MAIN OUTCOMES AND MEASURES:Cortical gyrification was assessed using local gyrification index in a vertexwise fashion across the entire cortical surface with correction for multiple testing using permutation analysis. Differences in local gyrification index were assessed between responders, nonresponders, and healthy controls. The effect of diagnosis (affective vs nonaffective psychosis) on the local gyrification index was also investigated in responders and nonresponders.RESULTS:Patients with first-episode psychosis showed a significant reduction in gyrification (hypogyria) across multiple brain regions compared with healthy controls. Interestingly, nonresponders showed prominent hypogyria at bilateral insular, left frontal, and right temporal regions when compared with responders (all clusters significant at P < .05). These effects were present for both affective and nonaffective psychoses.CONCLUSIONS AND RELEVANCE:Gyrification appears to be a useful predictor of antipsychotic treatment response. Early neurodevelopmental aberrations may predict unfavorable prognosis in psychosis, irrespective of the existing diagnostic boundaries.

"I am sane but he is mad": Insight and illness attributions to self and others in psychosis.

Abstract:We attempted to explore whether lack of insight in patients with psychosis is related to their genuine inability to recognise symptoms of mental illness as opposed to denial. We addressed this by examining participants' judgments of illness in vignettes in which they were either the protagonist or were commenting on others' behaviour. We recruited 44 first episode psychosis patients and 23 healthy controls to make judgements of specially constructed vignettes describing psychotic symptoms. Insight, Theory of Mind (ToM) and IQ was also measured. Patients' and controls' rating of vignettes overall did not differ significantly with respect to their attribution of mental illness. Patients and controls rated 2nd person vignettes similarly; patients were less likely to attribute mental illness to a character described in the 3rd person. This effect correlated with insight scores. Vignette judgments were significantly correlated with ToM performance but this was moderated by IQ. In conclusion, patients with lower insight tend to make the same attributions to others as to themselves, whilst healthy controls tend to think of mental illness as something seen in other people. There was no support for a 'denial' explanation for lack of insight in these patients.

Abstract:BACKGROUND:An association between social disadvantage and established psychosis is well documented in the literature, but there remains a lack of data on the social circumstances of patients before they became ill. We investigated whether social disadvantage at, and prior to, first contact with psychiatric services, is associated with psychosis.METHOD:We collected information on social disadvantage in childhood and adulthood from 278 cases presenting with their first episode of psychosis to the South London and Maudsley National Health Service Foundation Trust and from 226 controls recruited from the local population. Three markers of childhood social disadvantage and 3 markers of disadvantage in adulthood were analyzed.RESULTS:Long term separation from, and death of, a parent before the age of 17 years were both strongly associated with a 2- to 3-fold-increased odds of psychosis. Cases were also significantly more likely to report 2 or more markers of adult social disadvantage than healthy controls (OR = 9.03) at the time of the first presentation with psychosis, independent of a number of confounders. When we repeated these analyses for long-standing adult social disadvantage, we found that the strength of the association decreased but still remained significant for 1 year (OR = 5.67) and 5 years (OR = 2.57) prior to the first contact.CONCLUSIONS:Social disadvantage indexes exposure to factors operating prior to onset that increase the risk of psychosis, both during childhood and adulthood.

Abstract:BACKGROUND:Cannabis use is associated with an increased risk of psychosis. One study has suggested that genetic variation in the AKT1 gene might influence this effect.METHODS:In a case-control study of 489 first-episode psychosis patients and 278 control subjects, we investigated the interaction between variation at the AKT1 rs2494732 single nucleotide polymorphism and cannabis use in increasing the risk of psychosis.RESULTS:The rs2494732 locus was not associated with an increased risk of a psychotic disorder, with lifetime cannabis use, or with frequency of use. We did, however, find that the effect of lifetime cannabis use on risk of psychosis was significantly influenced by the rs2494732 locus (likelihood ratio statistic for the interaction = 8.54; p = .014). Carriers of the C/C genotype with a history of cannabis use showed a greater than twofold increased likelihood of a psychotic disorder (odds ratio = 2.18 [95% confidence interval: 1.12, 4.31]) when compared with users who were T/T carriers. Moreover, the interaction between the rs2494732 genotype and frequency of use was also significant at the 5% level (likelihood ratio = 13.39; p = .010). Among daily users, C/C carriers demonstrated a sevenfold increase in the odds of psychosis compared with T/T carriers (odds ratio = 7.23 [95% confidence interval: 1.37, 38.12]).CONCLUSIONS:Our findings provide strong support for the initial report that genetic variation at rs2494732 of AKT1 influences the risk of developing a psychotic disorder in cannabis users.

Sexual dysfunction in people with prodromal or first-episode psychosis.

Abstract:BACKGROUND:Sexual dysfunction is common in psychotic disorder but it is not clear whether it is intrinsic to the development of the illness or secondary to other factors.AIMS:To compare sexual function in people at ultra-high risk (UHR) of a psychotic disorder, patients with first-episode psychosis predominantly taking antipsychotic drugs and healthy volunteers.METHOD:Sexual function was assessed in a UHR group (n = 31), a group with first-episode psychosis (n = 37) and a matched control group of healthy volunteers (n = 56) using the Sexual Function Questionnaire.RESULTS:There was a significant effect of group on sexual function (P<0.001). Sexual dysfunction was evident in 50% of the UHR group, 65% of first-episode patients and 21% of controls. Within the UHR group, sexual dysfunction was more marked in those who subsequently developed psychosis than in those who did not. Across all groups the severity of sexual dysfunction was correlated with the severity of psychotic symptoms (P<0.001). Within the first-episode group there was no significant difference in sexual dysfunction between patients taking prolactin-raising v. prolactin-sparing antipsychotics.CONCLUSIONS:Sexual dysfunction is present prior to onset of psychosis, suggesting it is intrinsic to the development of illness unlikely to be related to the prolactin-raising properties of antipsychotic medication.

Abstract:Antipsychotic drugs act on the dopaminergic system (first-generation antipsychotics, FGA), but some also directly affect serotonergic function (second-generation antipsychotics, SGA) in the brain. Short and long-term effects of these drugs on brain physiology remain poorly understood. Moreover, it remains unclear whether any physiological effect in the brain may be different for FGAs and SGAs. Immediate (+3.30 h) and different effects of single-dose FGA (haloperidol, 3 mg) and a SGA (aripiprazole, 10 mg) on resting cerebral blood flow (rCBF) were explored in the same 20 healthy volunteers using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T) in a placebo-controlled, repeated measures design. Both antipsychotics increased striatal rCBF but the effect was greater after haloperidol. Both decreased frontal rCBF, and opposite effects of the drugs were observed in the temporal cortex (haloperidol decreased, aripiprazole increased rCBF) and in the posterior cingulate (haloperidol increased, aripiprazole decreased rCBF). Further increases were evident in the insula, hippocampus, and anterior cingulate after both antipsychotics, in the motor cortex following haloperidol and in the occipital lobe the claustrum and the cerebellum after aripiprazole. Further decreases were observed in the parietal and occipital cortices after aripiprazole. This study suggests that early and different rCBF changes are evident following a single-dose of FGA and SGA. The effects occur in healthy volunteers, thus may be independent from any underlying pathology, and in the same regions identified as structurally and functionally altered in schizophrenia, suggesting a possible relationship between antipsychotic-induced rCBF changes and brain alterations in schizophrenia.

Abstract:BACKGROUND:The high incidence of the metabolic syndrome in patients with psychosis is mainly attributed to antipsychotic treatment. However, it is also possible that psychological stress plays a role, inducing a chronic inflammatory process that may predispose to the development of metabolic abnormalities. We investigated the association between childhood maltreatment and inflammatory and metabolic biomarkers in subjects with first-episode psychosis and healthy controls.METHOD:Body mass index (BMI), weight and waist circumference were measured in 95 first-episode psychosis patients and 97 healthy controls. Inflammatory and metabolic markers were measured in a subsample of 28 patients and 45 controls. In all the subjects we collected information on childhood maltreatment and recent stressors.RESULTS:Patients with childhood maltreatment had higher BMI [25.0 (S.E.=0.6) kg/m2] and C-reactive protein (CRP) levels [1.1 (S.E.=0.6) mg/dl] when compared with healthy controls [23.4 (S.E.=0.4) kg/m2, p=0.030 and 0.2 (S.E.=0.1) mg/dl, p=0.009, respectively]. In contrast, patients without childhood maltreatment were not significantly different from healthy controls for either BMI [24.7 (S.E.=0.6) kg/m2, p=0.07] or CRP levels [0.5 (S.E.=0.2) mg/dl, p=0.25]. After controlling for the effect of BMI, the difference in CRP levels across the three groups remained significant (F 2,58=3.6, p=0.035), suggesting that the increase in inflammation was not driven by an increase in adipose tissue.CONCLUSIONS:Childhood maltreatment is associated with higher BMI, and increased CRP levels, in patients with a first-episode psychosis. Further studies need to confirm the mechanisms underlying the putative causal relationship between childhood maltreatment and higher BMI, and whether this is indeed mediated by increased inflammation.

Abstract:Calibration experiments precede multicenter trials to identify potential sources of variance and bias. In support of future imaging studies of mental health disorders and their treatment, the Neuro/PsyGRID consortium commissioned a calibration experiment to acquire functional and structural MRI from twelve healthy volunteers attending five centers on two occasions. Measures were derived of task activation from a working memory paradigm, fractal scaling (Hurst exponent) from resting fMRI, and grey matter distributions from T(1) -weighted sequences. At each intracerebral voxel a fixed-effects analysis of variance estimated components of variance corresponding to factors of center, subject, occasion, and within-occasion order, and interactions of center-by-occasion, subject-by-occasion, and center-by-subject, the latter (since there is no intervention) a surrogate of the expected variance of the treatment effect standard error across centers. A rank order test of between-center differences was indicative of crossover or noncrossover subject-by-center interactions. In general, factors of center, subject and error variance constituted >90% of the total variance, whereas occasion, order, and all interactions were generally <5%. Subject was the primary source of variance (70%-80%) for grey-matter, with error variance the dominant component for fMRI-derived measures. Spatially, variance was broadly homogenous with the exception of fractal scaling measures which delineated white matter, related to the flip angle of the EPI sequence. Maps of P values for the associated F-tests were also derived. Rank tests were highly significant indicating the order of measures across centers was preserved. In summary, center effects should be modeled at the voxel-level using existing and long-standing statistical recommendations.

Abstract:BACKGROUND:Brain morphometry is extensively used in cross-sectional studies. However, the difference in the estimated values of the morphometric measures between patients and healthy subjects may be small and hence overshadowed by the scanner-related variability, especially with multicentre and longitudinal studies. It is important therefore to investigate the variability and reliability of morphometric measurements between different scanners and different sessions of the same scanner.METHODS:We assessed the variability and reliability for the grey matter, white matter, cerebrospinal fluid and cerebral hemisphere volumes as well as the global sulcal index, sulcal surface and mean geodesic depth using Brainvisa. We used datasets obtained across multiple MR scanners at 1.5 T and 3 T from the same groups of 13 and 11 healthy volunteers, respectively. For each morphometric measure, we conducted ANOVA analysis and verified whether the estimated values were significantly different across different scanners or different sessions of the same scanner. The between-centre and between-visit reliabilities were estimated from their contribution to the total variance, using a random-effects ANOVA model. To estimate the main processes responsible for low reliability, the results of brain segmentation were compared to those obtained using FAST within FSL.RESULTS:In a considerable number of cases, the main effects of both centre and visit factors were found to be significant. Moreover, both between-centre and between-visit reliabilities ranged from poor to excellent for most morphometric measures. A comparison between segmentation using Brainvisa and FAST revealed that FAST improved the reliabilities for most cases, suggesting that morphometry could benefit from improving the bias correction. However, the results were still significantly different across different scanners or different visits.CONCLUSIONS:Our results confirm that for morphometry analysis with the current version of Brainvisa using data from multicentre or longitudinal studies, the scanner-related variability must be taken into account and where possible should be corrected for. We also suggest providing some flexibility to Brainvisa for a step-by-step analysis of the robustness of this package in terms of reproducibility of the results by allowing the bias corrected images to be imported from other packages and bias correction step be skipped, for example.

The different trajectories of antipsychotic response: Antipsychotics versus Placebo

Abstract:BACKGROUND:It is generally accepted that antipsychotics are more effective than placebo. However, it remains unclear whether antipsychotics induce a pattern or trajectory of response that is distinct from placebo. We used a data-driven technique, called growth mixture modelling (GMM), to identify the different patterns of response observed in antipsychotic trials and to determine whether drug-treated and placebo-treated subjects show similar or distinct patterns of response.METHOD:We examined data on 420 patients with schizophrenia treated for 6 weeks in two double-blind placebo-controlled trials using haloperidol and olanzapine. We used GMM to identify the optimal number of response trajectories; to compare the trajectories in drug-treated versus placebo-treated patients; and to determine whether the trajectories for the different dimensions (positive versus negative symptoms) were identical or different.RESULTS:Positive symptoms were found to respond along four distinct trajectories, with the two most common trajectories ('Partial responder' and 'Responder') accounting for 70% of the patients and seen proportionally in both drug- and placebo-treated. The most striking drug-placebo difference was in the 'Dramatic responders', seen only among the drug-treated. The response of negative symptoms was more modest and did not show such distinct trajectories.CONCLUSIONS:Trajectory models of response, rather than the simple responder/non-responder dichotomy, provide a better statistical account of how antipsychotics work. The 'Dramatic responders' (those showing >70% response) were seen only among the drug-treated and make a significant contribution to the overall drug-placebo difference. Identifying and studying this subset may provide specific insight into antipsychotic action.

Abstract:First-episode psychosis (FEP) patients show hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, but the mechanisms leading to this are still unclear. The aim of this study was to investigate the role of stress and antipsychotic treatment on diurnal cortisol levels, and on cortisol awakening response, in FEP. Recent stressful events, perceived stress and childhood trauma were collected in 50 FEP patients and 36 healthy controls using structured instruments. Salivary cortisol was obtained at awakening, at 15, 30, and 60min after awakening, and at 12 and 8pm. Patients experienced more recent stressful events, perceived stress and childhood trauma than controls (p<0.001). Patients had a trend for higher diurnal cortisol levels (p=0.055), with those with less than two weeks of antipsychotics showing significantly higher cortisol levels than both patients with more than two weeks of antipsychotics (p=0.005) and controls (p=0.002). Moreover, patients showed a blunted cortisol awakening response compared with controls, irrespectively of antipsychotic treatment (p=0.049). These abnormalities in patients were not driven by the excess of stressors: diurnal cortisol levels were negatively correlated with the number of recent stressful events (r=-0.36, p=0.014), and cortisol awakening response was positively correlated with a history of sexual childhood abuse (r=0.33, p=0.033). No significant correlations were found between perceived stress or severity of symptoms and cortisol levels, either diurnal or in the awakening response. Our study shows that antipsychotics normalize diurnal cortisol hyper-secretion but not the blunted cortisol awakening response in FEP; factors other than the excess of psychosocial stress explain HPA axis abnormalities in FEP.

Higher cortisol levels are associated with smaller left hippocampal volume in first-episode psychosis.

Abstract:This study investigated the relationship between cortisol secretion and hippocampal volume in first-episode psychosis and healthy controls. Hippocampal volume was measured by magnetic resonance imaging (MRI) in 24 first-episode psychosis patients and in 18 healthy controls, together with diurnal cortisol levels. Twelve patients received a second MRI scan at 3-month follow-up. Diurnal cortisol levels were inversely correlated with left hippocampal volume in patients, both at baseline and at follow-up, while no correlation was found in controls. Our findings suggest that smaller hippocampal volume in first-episode psychosis can partly be explained by stress-related processes in the brain, as measured by cortisol hyper-secretion.

Obsessive-compulsive disorder as a visual processing impairment.

Authors: Gonçalves OF, Marques TR, Lori NF, Sampaio A, Branco MC.

Medical Hypotheses, 2010

Abstract:OCD has been hypothesized to involve the failures in both cognitive and behavioral inhibitory processes. There is evidence that the hyperactivation of cortical-subcortical pathways may be involved in the failure of these inhibitory systems associated with OCD. Despite this consensus on the role of frontal-subcortical pathways in OCD, recent studies have been showing that brain regions other than the frontal-subcortical loops may be needed to understand the different cognitive and emotional deficits in OCD. Some studies have been finding evidence for decreased metabolic activity in areas such as left inferior parietal and parieto-occipital junction suggesting the possible existence of visual processing deficits. While there has been inconsistent data regarding visual processing in OCD, recent studies have been claiming that these patients have abnormal patterns of visual processing social rich stimuli, particularly emotional arousing stimuli. Thus, in this article, we hypothesize that the fronto-subcortical activation consistently found in OCD may be due to a deactivation of occipital/parietal regions associated with visual-perceptual processing of incoming social rich stimuli. Additionally, this dissociation may be more evident as the emotional intensity of the social stimulus increases.

Power calculations for multicenter imaging studies controlled by the false discovery rate.

Abstract:Magnetic resonance imaging (MRI) is widely used in brain imaging research (neuroimaging) to explore structural and functional changes across dispersed neural networks visible only via multisubject experiments. Multicenter investigations are an effective way to increase recruitment rates. This article describes image-based power calculations for a two-group, cross-sectional design specified by the mean effect size and its standard error, sample size, false discovery rate (FDR), and size of the network (i.e., proportion of image locations) that truly demonstrates an effect. Minimum sample size (for fixed effect size) and the minimum effect size (for fixed sample size) are calculated by specifying the acceptable power threshold. Within-center variance was estimated in five participating centers by repeat MRI scanning of 12 healthy participants from whom distributions of gray matter were estimated. The effect on outcome measures when varying FDR and the proportion of true positives is presented. Their spatial patterns reflect within-center variance, which is consistent across centers. Sample sizes 3-6 times larger are needed when detecting effects in subcortical regions compared to the neocortex. Hypothesized multicenter studies of patients with first episode psychosis and control participants were simulated with varying proportions of the cohort recruited at each center. There is little penalty to sample size for recruitment at five centers compared to the center with the lowest variance alone. At 80% power 80 participants per group are required to observe differences in gray matter in high variance regions.

Abstract:First-episode psychosis (FEP) patients show hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, but the mechanisms leading to this are still unclear. The aim of this study was to investigate the role of stress and antipsychotic treatment on diurnal cortisol levels, and on cortisol awakening response, in FEP. Recent stressful events, perceived stress and childhood trauma were collected in 50 FEP patients and 36 healthy controls using structured instruments. Salivary cortisol was obtained at awakening, at 15, 30, and 60min after awakening, and at 12 and 8pm. Patients experienced more recent stressful events, perceived stress and childhood trauma than controls (p<0.001). Patients had a trend for higher diurnal cortisol levels (p=0.055), with those with less than two weeks of antipsychotics showing significantly higher cortisol levels than both patients with more than two weeks of antipsychotics (p=0.005) and controls (p=0.002). Moreover, patients showed a blunted cortisol awakening response compared with controls, irrespectively of antipsychotic treatment (p=0.049). These abnormalities in patients were not driven by the excess of stressors: diurnal cortisol levels were negatively correlated with the number of recent stressful events (r=-0.36, p=0.014), and cortisol awakening response was positively correlated with a history of sexual childhood abuse (r=0.33, p=0.033). No significant correlations were found between perceived stress or severity of symptoms and cortisol levels, either diurnal or in the awakening response. Our study shows that antipsychotics normalize diurnal cortisol hyper-secretion but not the blunted cortisol awakening response in FEP; factors other than the excess of psychosocial stress explain HPA axis abnormalities in FEP.

Abstract:BACKGROUND:People who use cannabis have an increased risk of psychosis, an effect attributed to the active ingredient Delta 9-tetrahydrocannabinol (Delta 9-THC). There has recently been concern over an increase in the concentration of Delta 9-THC in the cannabis available in many countries.AIMS:To investigate whether people with a first episode of psychosis were particularly likely to use high-potency cannabis.METHOD:We collected information on cannabis use from 280 cases presenting with a first episode of psychosis to the South London & Maudsley National Health Service (NHS) Foundation Trust, and from 174 healthy controls recruited from the local population.RESULTS:There was no significant difference between cases and controls in whether they had ever taken cannabis, or age at first use. However, those in the cases group were more likely to be current daily users (OR = 6.4) and to have smoked cannabis for more than 5 years (OR = 2.1). Among those who used cannabis, 78% of the cases group used high-potency cannabis (sinsemilla, 'skunk') compared with 37% of the control group (OR 6.8).CONCLUSIONS:The finding that people with a first episode of psychosis had smoked higher-potency cannabis, for longer and with greater frequency, than a healthy control group is consistent with the hypothesis that Delta 9-THC is the active ingredient increasing risk of psychosis. This has important public health implications, given the increased availability and use of high-potency cannabis.

Brain blood flow SPET imaging in heroin abusers.

Abstract:To assess whether chronic heroin abuse may generate vascular central nervous deficits, we studied the profile of vascular alterations in 17 heroin addicts (14 males mean age 31 years, range 23-39 years and 3 females mean age 33 years, range 30-35 years) before and, in one of them, 10 weeks after an ultra-rapid heroin detoxification. Using the functional technique of single-photon emission tomography (SPET) with 740 MBq of (99m)Tc-hexametazine (HMPAO) and computational brain-mapping techniques by means of a Talairach analysis, we determined the pattern of vascular brain alterations associated with chronic heroin abuse. Compared with controls, subjects who had used heroin chronically showed a decrease of global brain perfusion that was more significant in the frontal cortex-mainly in orbito-frontal regions, as well as in the occipital and temporal lobes. All patients showed marked asymmetric perfusion of the basal ganglia and the majority of them showed also an asymmetric perfusion of cerebellum. In addition, there were small activated areas dispersed in the occipital lobe (3 of 17) and apex region (4 of 17). In conclusion, decreased perfusion in heroin addicts was found in regions involved in the control of attention, motor speed, memory and visual-spatial processing. The prefrontal cortex is involved in decision making and inhibitory control, processes disturbed in heroin addicts who have stopped heroin consumption. A reduction in regional perfusion may reflect ongoing subtle neurocognitive deficits, which are consistent with the maintenance of asymmetry of the basal nuclei.

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Dr. Reis Marques is a psychiatrist in London with over 12 years of experience in the treatment of psychiatric disorders and recognised amongst his colleagues as an expert in the diagnosis and treatment of mental illness.

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Dr. Reis Marques offer a full diagnosis and treatment of all general psychiatric conditions such as Depression, Anxiety Disorders, Bipolar Disorder, OCD, ADHD, Alcohol and Drug Dependence and Psychotic Disorders.